BAG3 AS A REGULATOR OF CELL MOTILITY

BAG3 作为细胞运动的调节剂

• 批准号: 6874990
• 负责人: SHINICHI TAKAYAMA
• 金额: $ 5.81万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874990
• 关键词: 3T3 cells; SCID mouse; actins; apoptosis; athymic mouse; autoradiography; biological signal transduction; biomarker; cell motility; cell proliferation; cytoskeleton; gene expression; heat shock proteins; immunofluorescence technique; immunoprecipitation; mass spectrometry; metastasis; molecular chaperones; neoplasm /cancer invasiveness; neoplastic transformation; protein protein interaction; protooncogene; tissue /cell culture; transport proteins; western blottings

DESCRIPTION (provided by applicant): BAG3 binds to and regulates Hsp70 function (Takayama, et al. J Biol Chem 274: 781, 1999). The BAG3 protein contains a WW domain and a proline-rich region with SH3-binding motifs, suggesting that it may interact with proteins relevant to submembranous signal transduction, recruiting Hsp70 to signaling complexes and altering cell responses. BAG3 binds to several cellular proteins including a GDP Exchange Factor (GEF) and SH3-containing signal transducing proteins, in addition to 70-kDa heat shock proteins. BAG3 over-expression in Balb/c 3T3 fibroblasts induces transformation and BAG3 over-expression has been observed in human cancers, especially pancreatic cancer. We speculate therefore that BAG3 represents a novel proto-oncogene that may affect cell transformation, anchorage-independent growth, or other processes relevant to the malignant phenotype. Also we have found that BAG3 over-expression increases motility of Cos7 cell. Moreover, homozygous bag3 deficient mouse embryonic fibroblasts exhibit dysregulation of actin cytoskeleton and abnormal motility. Experiments are proposed to explore the molecular mechanism of the BAG3 protein. (1) Investigating how BAG3 controls cytoskeleton and determining what domains of BAG3 are required including; (2) Exploring the functional significance of interactions of BAG3 with GEF, SH3 proteins and Hsp70 proteins; and (3) Exploring BAG3 expression in cancer and its role in malignant transformation. These studies will provide insights into the oncogenic properties of BAG3 and may assist in finding new targets for cancer therapy.

描述（由申请人提供）： BAG3 结合并调节 Hsp70 功能（Takayama 等人，J Biol Chem 274：781，1999）。 BAG3蛋白含有WW结构域和富含脯氨酸的区域，并具有SH3结合基序，这表明它可能与膜下信号转导相关的蛋白质相互作用，将Hsp70招募到信号复合物中并改变细胞反应。 BAG3 与多种细胞蛋白结合，包括 GDP 交换因子 (GEF) 和含有 SH3 的信号转导蛋白，以及 70 kDa 热休克蛋白。 Balb/c 3T3 成纤维细胞中 BAG3 过度表达会诱导转化，并且在人类癌症（尤其是胰腺癌）中观察到 BAG3 过度表达。因此，我们推测 BAG3 代表一种新的原癌基因，可能影响细胞转化、贴壁依赖性生长或与恶性表型相关的其他过程。我们还发现 BAG3 过表达会增加 Cos7 细胞的运动性。此外，纯合 bag3 缺陷小鼠胚胎成纤维细胞表现出肌动蛋白细胞骨架失调和运动异常。拟通过实验探索BAG3蛋白的分子机制。 (1) 研究BAG3如何控制细胞骨架并确定需要BAG3的哪些结构域，包括； (2)探讨BAG3与GEF、SH3蛋白和Hsp70蛋白相互作用的功能意义； (3)探索BAG3在癌症中的表达及其在恶性转化中的作用。这些研究将深入了解 BAG3 的致癌特性，并可能有助于寻找癌症治疗的新靶点。